Common and divergent features of galactose-1-phosphate and fructose-1-phosphate toxicity in yeast

Patrick A. Gibney, Ariel Schieler, Jonathan C. Chen, Jessie M. Bacha-Hummel, Maxim Botstein, Matthew Volpe, Sanford J. Silverman, Yifan Xu, Bryson D. Bennett, Joshua D. Rabinowitz, David Botstein, David G. Drubin

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4 Scopus citations

Abstract

Toxicity resulting from accumulation of sugar-phosphate molecules is an evolutionarily conserved phenomenon, observed in multiple bacterial and eukaryotic systems, including a number of human diseases. However, the molecular mechanisms involved in sugar-phosphate toxicity remain unclear. Using the model eukaryote Saccharomyces cerevisiae, we developed two systems to accumulate human disease-associated sugar-phosphate species. One system utilizes constitutive expression of galactose permease and galactose kinase to accumulate galactose-1-phosphate, while the other system utilizes constitutive expression of a mammalian ketohexokinase gene to accumulate fructose-1-phosphate. These systems advantageously dissociate sugar-phosphate toxicity from metabolic demand for downstream enzymatic products. Using them, we characterized the pathophysiological effects of sugar-phosphate accumulation, in addition to identifying a number of genetic suppressors that repair sugar-phosphate toxicity. By comparing the effects of different sugar-phosphates, and examining the specificity of genetic suppressors, we observed a number of striking similarities and significant differences. These results suggest that sugar-phosphates exert toxic effects, at least in part, through isomer-specific mechanisms rather than through a single general mechanism common to accumulation of any sugar-phosphate.

Original languageEnglish (US)
Pages (from-to)897-910
Number of pages14
JournalMolecular biology of the cell
Volume29
Issue number8
DOIs
StatePublished - Apr 15 2018

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Gibney, P. A., Schieler, A., Chen, J. C., Bacha-Hummel, J. M., Botstein, M., Volpe, M., Silverman, S. J., Xu, Y., Bennett, B. D., Rabinowitz, J. D., Botstein, D., & Drubin, D. G. (2018). Common and divergent features of galactose-1-phosphate and fructose-1-phosphate toxicity in yeast. Molecular biology of the cell, 29(8), 897-910. https://doi.org/10.1091/mbc.E17-11-0666